This K award will be integral in the development of Dr. Honea's career plan, which was designed to extend her neuroimaging investigations schizophrenia, to studying complex genetic and environmental interactions and their impact on imaging markers of neurodegeneration in Alzheimer's disease. While Dr. Honea has successfully applied VBM methodologies to ask initial questions about AD risk, she needs more advanced training in Alzheimer's disease clinical methodology, genetics, and methodology in exercise physiology and fitness. Dr. Honea will work in the department of Neurology at the University of Kansas Medical Center (KUMC) under mentorship of Dr. Jeffrey Burns to learn Alzheimer's disease clinical methodology. Dr. Honea will capitalize on several of the University of Kansas' research strengths: the Hoglund Brain Imaging Center, Genetics Research in the Molecular and Integrative Physiology Department, the General Clinical Research Center, and the Alzheimer's and Memory Program. The proposed additional training will allow her to effectively study the role of genetic variation in Alzheimer's disease in large datasets, such as the ADNI and Washington University ADRC datasets, and then apply those results to the study of gene x environment interactions. In order to ask more complex questions about the role of genetic variation in Alzheimer's Disease neurodegeneration, she will need to develop new collaborations with AD genetics expert Alison Goate, PhD. Additional mentored training in genetics under Dr. Goate will give her the ability to investigate complex interactions with other genes, and environmental moderators of stress and protection relevant to aging research. Training in imaging genetics will be provided by Dr. Daniel Weinberger, Chief of the Clinical Brain Disorders Branch and Director of the Genes, Cognition, and Psychosis program at NIMH. Additional technical training will be provided by Cary Savage, PhD in fMRI experimental design, analysis, and the application of fMRI to Alzheimer's populations. The combination of well-funded and experienced mentors, education, laboratory training, and clinical experience provides an ideal vehicle for advancing Dr. Honea's career goals. Dr. Honea's overall goal is to conduct a series of imaging analyses to begin examining genetic variation and the influence of this variation on brain structure and function, and its relationship to CR fitness. As a model system to begin examining gene by environment interactions, we have identified several candidate genes associated with AD risk (BDNF, APOE, CLU, PICALM, CR1, TOMM40) 21, 22, and will take them through a three-step process. Our overall hypothesis is that CR fitness may moderate the neurodegenerative effect of genetic variation in one or more genes on MRI phenotypes of AD progression. Aim 1: Gene - Brain Structure: Assess the relationship of selected candidate genes with MRI phenotypes and cognitive markers of AD progression. We will first use ADNI data to characterize the relationship between each single nucleotide polymorphism (SNP) and baseline regional brain volume, rates of hippocampal and whole brain atrophy, and change in ADAS-COG in all subject groups (ND, MCI, and AD) for maximum power. We will then replicate all tests in the longitudinal Washington University ADRC dataset. These secondary data analyses in two well-characterized datasets will allow us to verify pertinent gene to brain structure relationships. Aim 2: Gene x Environment - Brain Structure: Examine whether CR fitness moderates the relationship between genetic variation and brain neurodegeneration. We have demonstrated that increased levels of CR fitness may protect brain volume in early AD 51, 52, although the mechanism for this is unknown. The beneficial effects of CR fitness may moderate the relationship between genetic variation and neurodegeneration53-57. We will test whether CR fitness moderates the relationship between candidate SNPs related to brain structure, and hippocampal and whole brain atrophy in a longitudinal dataset. Aim 3: Gene x Environment - Brain Function: Examine the influence of genetic variation on the relationship of CR Fitness with fMRI markers of neural activity. CR fitness 30, 51, 52and genetic variation58, 59 have independently been shown to moderate neural activity during learning and memory, although their interaction is unexplored. We will use fMRI to measure the impact of fitness on hippocampal learning and memory, and characterize whether key genes associated with hippocampal structure and function moderate this relationship. The proposed research will first characterize genetic mechanisms influencing hippocampal structure and function, then test for gene-environment interactions that might moderate brain neurodegeneration. While the initial focus is on genes such as APOE, based on its relationship to the MRI endophenotypes of AD, and BDNF based on its involvement in exercise-related brain changes,60, 61 these analyses will provide a strategy and foundation from which to advance Dr. Honea's independent research on gene by environment interactions relevant for brain health. The marriage of molecular genetics with environmental factors will provide a fertile direction for translational aging research and a step towards identifying future therapies for AD62.